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Journal of Lipid Research, Vol. 43, 1192-1200, August 2002
Copyright © 2002 by Lipid Research, Inc.
Limb malformations of rat fetuses exposed to a distal inhibitor of cholesterol biosynthesis
INSERM Unité 538, CHU Saint Antoine, 27 rue Chaligny, Paris 75012, France
1 To whom correspondence should be addressed. e-mail: wolf{at}ccr.jussieu.fr
Triparanol, an inhibitor of desmosterol 
24 reductase, produces a high rate of limb malformations in rat fetuses exposed at gestational day 10 (gd 10) to a single oral dose (150–200 mg/kg) given to the pregnant dam. AY9944, another efficient distal inhibitor of cholesterol biosynthesis that blocks dehydrocholesterol 7 reductase, produces a similar degree of cholesterol depletion but fewer malformations. Gas liquid chromatography–mass spectrometry (GC-MS) profiling of the sterols in the serum of the dams and in extracted embryos shows that in addition to desmosterol 24 reductase inhibition the conversion of 8 to 7 unsaturated sterols is also blocked by Triparanol. Therefore, the inhibitor induces the accumulation of desmosterol (8 cholesten-3ß-ol, 8-dehydrocholesterol) and zymosterol (8, 24 cholestadien-3ß-ol) in embryo tissues. The high concentration of the teratogenic drug assayed in the embryos at three successive gestational days (10–30 µg/g) is thought to cause the blockade in both 24 reductase and 8-7 isomerase, which results in the particular profile of aberrant sterols.
Comparison of the animal model with human syndromes, including limb osseous and skeleton perturbations, suggests a combination of desmosterol and 8 unsaturated sterols as being involved in the deleterious influence on limb bone formation.
Abbreviations: GC-MS, gas liquid chromatography-mass spectrometry; gd, gestational day
Supplementary key words limb patterning • Sonic Hedgehog • osteogenesis • Indian Hedgehog • chondrodysplasia • desmosterolosis • 8 cholesten-3ß-ol • zymosterol • Triparanol
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